Assessment of Scotopic Function in Rod–Cone Inherited Retinal Degeneration With the Scotopic Macular Integrity Assessment

Purpose: The scotopic macular integrity assessment (S-MAIA) can perform scotopic assessment to detect localized changes to scotopic rod and cone function. This study is an exploratory investigation of the feasibility of using the S-MAIA in a rod–cone dystrophy population to identify the pattern of loss in scotopic photoreceptor function. Methods: Twenty patients diagnosed with a rod–cone dystrophy underwent visual acuity testing, full-field stimulus threshold assessment, and multiple S-MAIA tests after dark adaptation periods of 20 minutes and 45 minutes performed separately. Only right eyes were tested. Three tests were performed following a learning test. A Bland–Altman analysis was used to assess repeatability and agreement between tests after the two time periods. Spatial interpolation maps were created from the group plots to display the pattern of rod and cone loss. Results: Learning effects took place between testing sessions 1 and 2 but not 2 and 3. Limits of agreement were larger in the patient eyes than control eyes, but within previously reported values. Using longer adaptation time of 45 minutes did not offer a significant advantage over 20 minutes. Patterns for the cyan and red sensitivities were different, indicating different patterns of loss for rods and cones. Conclusions: A dark adaptation time of 20 minutes before testing is sufficient for thresholding. The S-MAIA is suitable for use in patients with a logarithm of the minimum angle of resolution vision of at least 0.7 and provides a viable outcome measure for patients with rod–cone dystrophies and preserved central vision. The spatial information about scotopic function from the S-MAIA provides information about disease processes and progression. Translational Relevance: There is a need for scotopic measures for use in clinical trials. Scotopic microperimetry works well in patients with early disease, allowing the extension of recruitment criteria for novel therapies of rod–cone dystrophies

Exploring the Variable Phenotypes of <i>RPGR</i> Carrier Females in Assessing Their Potential for Retinal Gene Therapy

Inherited retinal degenerations are the leading cause of blindness in the working population. X-linked retinitis pigmentosa (XLRP), caused by mutations in the Retinitis pigmentosa GTPase regulator (RPGR) gene is one of the more severe forms, and female carriers of RPGR mutations have a variable presentation. A retrospective review of twenty-three female RPGR carriers aged between 8 and 76 years old was carried out using fundoscopy, autofluorescence imaging (AF), blue reflectance (BR) imaging and optical coherence tomography (OCT). Confirmation of the genetic mutation was obtained from male relatives or Sanger genetic sequencing. Fundus examination and AF demonstrate phenotypic variability in RPGR carriers. The genetic mutation appears indeterminate of the degree of change. We found four distinct classifications based on AF images to describe RPGR carriers; normal (N) representing normal or near-normal AF appearance (n = 1, 4%); radial (R) pattern reflex without pigmentary retinopathy (n = 14, 61%); focal (F) pigmentary retinopathy (n = 5, 22%) and; male (M) phenotype (n = 3, 13%). The phenotypes were precisely correlated in both eyes (rs = 1.0, p &lt; 0.0001). Skewed X-inactivation can result in severely affected carrier females&#8212;in some cases indistinguishable from the male pattern and these patients should be considered for RPGR gene therapy. In the cases of the male (M) phenotype where the X-inactivation was skewed, the pattern was similar in both eyes, suggesting that the mechanism is not truly random but may have an underlying genetic basis

Preliminary results in 18 patients undergoing retinal gene therapy for X-linked retinitis pigmentosa with codon-optimized AAV8-RPGR

Purpose: To investigate the safety and efficacy of adeno-associated viral vector (AAV8) encoding retinitis pigmentosa GTPase regulator (RPGR) for X-linked retinitis pigmentosa (XLRP).Methods: This study (ClinicalTrials. gov ID NCT03116113) is being conducted in 2 Parts: Part I is a Phase 1 dose-escalation study to identify the maximum tolerated dose (MTD); Part II is a Phase 2/3, assessor-masked, dose-expansion study. In Part I, subjects with genetically confirmed RPGR-associated XLRP were administered a sub-retinal dose of AAV8-RPGR. The vector used a rhodopsin kinase promoter to drive expression of a codon-optimized sequence that generated the correct full length RPGR protein. A 3+ 3 escalation scheme was used, with 3 subjects/dose (5× 10 9, 1× 10 10, 5× 10 10, 1× 10 11, 2.5× 10 11, and 5× 10 11 gp). Part I endpoints were safety (adverse events [AEs], dose-limiting toxicities [DLTs], ophthalmic

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR

Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/: NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.</p